Ji Xingzhao, Xue Fuyuan, Wang Ying, Gao Dexuan, Sun Jian, Dong Tianyi, Mu Qian, Xu Quanlin, Sun Shengnan, Liu Yi, Wan Qiang
Shandong Provincial Key Medical and Health Laboratory of cell metabolism, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Cell Death Dis. 2025 Aug 26;16(1):646. doi: 10.1038/s41419-025-07896-3.
Renal cell carcinoma (RCC) is a common urological tumor, with clear cell renal cell carcinoma (ccRCC) being the most prevalent subtype. Metabolic reprogramming plays a critical role in ccRCC progression, making it a promising target for therapeutic intervention, though effective treatments remain unavailable. Our previous studies have shown that mitochondrial ribosomal protein L12 (MRPL12) contributes to various metabolic diseases, including diabetic kidney disease and HCC, by regulating mitochondrial biosynthesis. In this study, we demonstrated that MRPL12 is acetylated at lysine 163 (K163) in ccRCC cells, a key modification that influences its regulatory effect on mitochondrial metabolism. Mechanistically, we clarified that acetylation at the K163 site enhances mitochondrial biosynthesis by promoting MRPL12's binding to POLRMT, which subsequently increases mitochondrial metabolism and suppresses cellular glycolysis. Additionally, we found that MRPL12 K163 acetylation levels were significantly downregulated in ccRCC and that restoring this acetylation inhibited ccRCC progression in both in vitro and in vivo models. Furthermore, we demonstrated that the acetyltransferase TIP60 and the deacetylase SIRT5 bind to MRPL12 and regulate its acetylation. These findings highlight K163 acetylation as a critical site for MRPL12-mediated regulation of mitochondrial metabolism and reveal that this modification inhibits renal cancer development by promoting mitochondrial biosynthesis, reducing glycolysis, and driving metabolic reprogramming. This study suggests a potential therapeutic strategy for targeting MRPL12 acetylation in ccRCC.
肾细胞癌（RCC）是一种常见的泌尿系统肿瘤，其中透明细胞肾细胞癌（ccRCC）是最常见的亚型。代谢重编程在ccRCC进展中起关键作用，使其成为治疗干预的一个有前景的靶点，尽管目前仍缺乏有效的治疗方法。我们之前的研究表明，线粒体核糖体蛋白L12（MRPL12）通过调节线粒体生物合成，参与包括糖尿病肾病和肝癌在内的多种代谢性疾病。在本研究中，我们证明了ccRCC细胞中的MRPL12在赖氨酸163（K163）处发生乙酰化，这一关键修饰影响其对线粒体代谢的调节作用。机制上，我们阐明K163位点的乙酰化通过促进MRPL12与POLRMT的结合来增强线粒体生物合成，进而增加线粒体代谢并抑制细胞糖酵解。此外，我们发现ccRCC中MRPL12 K163的乙酰化水平显著下调，恢复这种乙酰化在体外和体内模型中均抑制了ccRCC的进展。此外，我们证明了乙酰转移酶TIP60和去乙酰化酶SIRT5与MRPL12结合并调节其乙酰化。这些发现突出了K163乙酰化是MRPL12介导的线粒体代谢调节的关键位点，并揭示这种修饰通过促进线粒体生物合成、减少糖酵解和驱动代谢重编程来抑制肾癌发展。本研究提出了一种针对ccRCC中MRPL12乙酰化的潜在治疗策略。
